Findings of an international clinical study published in The Lancet in 2017 suggest that 3.0mg of the drug liraglutide, may reduce diabetes risk by 80% in individuals with pre-diabetes and obesity, and thereby significantly contribute to the prevention of type-2 diabetes (T2DM). The study investigated whether 3.0mg of liraglutide would delay the onset of T2DM safely in people with pre-diabetes.

Liraglutide is the active solution in a drug marketed as Victoza, which obtained FDA approval in 2010. Victoza is available in 6 mg/ml pre‑filled pens, and is used as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. Victoza is used also as an add-on to other diabetes medicines, when these, together with exercise and diet, are not providing adequate control of blood glucose.

Pre-diabetes

Pre-diabetes is a condition that develops when your blood sugar levels are at the very high end of the normal range, but not quite high enough for a diagnosis of T2DM. Risk factors include age, weight and ethnicity. People of South Asian origin are up to six times more likely to develop pre-diabetes as a genetic susceptibility means they start to develop insulin resistance at a much lower Body Mass Index (BMI).With pre-diabetes your body begins to have trouble using the hormone insulin, which is necessary to transport glucose, which your body uses for energy, into your cells via the bloodstream. Pre-diabetes means that your body either does not make enough insulin or it does not use it well (insulin resistance).If you do not have enough insulin or if you are insulin resistant, you can build up too much glucose in your blood, leading to higher-than-normal blood glucose level and perhaps pre-diabetes. Blood glucose is measured using a test called HbA1c, which provides a picture of your blood sugar levels over the past two to three months. It counts the number of glucose molecules stuck to the red blood cells, which reveals how much sugar you have carried in your blood over the two to three month lifespan of the red blood cell. If your blood sugar is between 5.7 to 6.4%, this is called pre-diabetes (6.5 is officially diabetes). Dr Roni Sharvanu Saha, a consultant in acute medicine, diabetes and endocrinology at St George's Hospital, London describes pre-diabetes:

Prevalence and cost

It is estimated that 35% of adults in the UK, and 50% in the US now have pre-diabetes. Around 5-10% of these will progress to "full-blown" T2DM in any given year. Because there are no obvious symptoms for pre-diabetes the overwhelming majority of people with the condition do not know they have it, and are not aware of the long-term risks to their health, which include T2DM and its complications: heart attack, stroke, kidney failure, blindness and lower limb amputation. Over the past decade, the prevalence of T2DM has increased by almost two-thirds, and is now one of the world’s most common long-term health conditions.

An estimated £14bn is spent each year on treating diabetes and its complications in the UK. Treating obesity-linked illnesses costs £10bn a year. The annual medical cost of treating diabetes in the US is about US$176bn, and the cost of diabetes in reduced productivity is some US$69bn each year.

The gut-brain axis

The study published in The Lancet was led by John Wilding, Professor of Medicine, University of Liverpool, and is a continuation of work he started in 1996 when part of a team at Hammersmith Hospital in London, which first showed that the hormone GLP-1, on which liraglutide is based, was involved in the control of food intake.

Over the past two decades scientists have increased their understanding of the two-way communications between the gut and the brain, not only through nerve connections between the organs, but also through biochemical signals, such as hormones that circulate in the body. Dr Sufyan Hussain, Specialist Registrar and Honorary Clinical Lecturer in Diabetes, Endocrinology and Metabolism at Imperial College London, describes the gut-brain axis.

Targeting gut-brain pathways

An increasing number of different gut microbial species are now postulated to regulate brain function in health and disease. The westernized diet, which is high in saturated fats, red meats, and carbohydrates, and low in fresh fruits and vegetables, whole grains, seafood, and poultry, is hypothesized to be the cause of high obesity levels in many countries. For example, 63% and 69% of adults in the UK and US respectively are either overweight or obese, and therefore at risk of T2DM. Experimental and epidemiological evidence suggest that the gut microbiota is responsible for significant immunologic, neuronal, and endocrine changes that lead to obesity. The gut–brain axis influences obesity, and researchers such as Wilding have targeted communication pathways between the nervous system and the digestive system in an attempt to treat metabolic disorders.

Bariatric surgery and diabetes

A previousHealthPad Commentary describes how bariatric surgery is associated with gut-brain signals, which promote the remission of diabetes in patients. Many of the mechanisms that underlie how bariatric surgery produces metabolic benefits remain unclear, but researchers do know that such surgical procedures elevate levels of the hormones peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) that help to reduce appetite and have effects on the central nervous system.

Liraglutide

Liraglutide is a GLP-1 receptor agonist, which interacts with the part of the brain that controls appetite and energy intake. The drug slows food leaving the stomach, helps prevent your liver from making too much sugar, and helps the pancreas to produce more insulin when your blood sugar levels are high. The most common side effects with liraglutide are nausea and diarrhoea.

The clinical study

The three-year study followed 2,254 adults with pre-diabetes at 191 research sites in 27 countries worldwide. Participants were randomly allocated to either liraglutide or a placebo delivered by injection under the skin once daily for 160 weeks. Participants in the study were also placed on a reduced calorie diet and advised to increase their physical activity. The study showed that three years of continuous treatment with once-daily 3.0mg of liraglutide, in combination with diet and increased physical activity, reduces the risk of developing T2DM by 80% and results in greater sustained weight loss compared to the placebo.

"On the basis of our findings, liraglutide 3.0mg can provide us with a new therapeutic approach for patients with obesity and pre-diabetes to substantially reduce their risk of developing type 2 diabetes and its related complications . . . . It is very exciting to see a laboratory observation translated into a medicine that has the potential to help so many people, even though it has taken over 20 years,” says Wilding.

World’s first nationwide diabetes prevention program

NHS England, Public Health England and Diabetes UK launched the world’s first nationwide diabetes prevention strategy, Healthier You, in 2016. It provides personal coaches to educate people at risk of T2DM in healthy eating and lifestyle, and personal trainers to provide bespoke physical exercise programs that are expected to help people lose weight. By 2020 Healthier You expects to be rolled out to the whole country with 100,000 referrals available each year after that.

Extrapolating from previous studies

International clinical studies have shown evidence that lifestyle interventions such as those used in Healthier You can prevent or delay the onset of T2DM. However, the validity of generalizing the results of previous prevention studies is uncertain. Interventions that work in some societies may not work in others, because social, economic, and cultural forces influence diet and exercise. The UK’s Public Accounts Committee has expressed doubts about the way Healthier You is setting about its task, and has warned that, "By itself, it will not be enough to stem the rising number of people with diabetes".

Failure of the diabetes establishment and the Public Accounts Committee

Healthier You is a slow, labor-intensive and expensive program, which is unlikely to have more than a relatively small impact.Let us explain. Assume that after 2020 Healthier You obtains its projected annual 100,000 referrals, and that they all successfully reduce their blood glucose levels with diet and exercise. Also assume that the prevalence of pre-diabetes in the UK does not increase, (which is not the case) then Healthier You will take more than 110 years to counsel the estimated 11.5m people in the UK with pre-diabetes: which is long after most people with pre-diabetes would have died from natural causes.

21st century communications

Successfully changing the diets and lifestyles of the 11.5m people in the UK believed to have pre-diabetes, and slowing their progression to T2DM will require 21st century technologies. Inexpensive and ubiquitous healthcare technologies used to educate and support diets and lifestyles abound. Increasingly people are demanding devices that track weight, blood pressure, daily exercise and diet. From apps to wearable’s, healthcare technology lets people feel in control of their health, while also providing health professionals with more patient data than ever before. With more than 100,000 healthcare apps, rapid growth in wearables, and 75% of the UK population now owning a smartphone, digital technology is well positioned to significantly improve healthcare education and management.

Takeaways

Has Healthier You missed the elephant in the room? Wilding’s study suggests that an exercise and diet program needs to be complemented with a sustained program of appropriate drugs if we are to reduce those with pre-diabetes from progressing to full blown T2DM. Further, simple arithmetic suggests that the education element of such a strategy about diet and lifestyle should leverage ubiquitous 21st century communications infrastructures if they are to be efficacious.

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Obesity is one of the most serious global public health challenges of the 21st century and a major cause of type-2 diabetes (T2DM), a life-threatening illness, which costs billions

60% of adults in the UK are either overweight or obese, 74% in the US

Low calorie diets and exercise are difficult to sustain and therefore tend to fail as treatment options

Conventional treatments for T2DM have failed to dent the vast and escalating burden of the condition, so interest is increasing in alternative treatment options

Bariatric (stomach reduction) surgery is a therapy for obesity, which has been shown to “cure” T2DM

In 2016, 45 international health organizations called for bariatric surgery as a treatment for T2DM

Is bariatric surgery the biggest step forward in T2DM treatment in 100 years?

Weight loss surgery to treat T2DM

It is five minutes to midnight for healthcare systems struggling in vein to reduce the vast and escalating burden of type-2 diabetes (T2DM). Doing more of the same is no longer an option. Given the lack of alternatives, experts are calling for an increase in bariatric surgery because it has been shown to “cure” T2DM.

Bariatric surgery not only reduces weight, it also improves glycemic control by a combination of enforced caloric restriction, enhanced insulin sensitivity, and increased insulin secretion with a consequent reduction in the symptoms of T2DM.

In the video below Kenneth D’Cruz, Senior Consultant Gastroenterological Surgeon at Narayana Health, India describes bariatric surgery, which refers to a range of procedures including gastric bypass, gastric sleeve, gastric band,and gastric balloon.Such procedures are often performed to limit the amount of food that an individual can consume, and are mainly used to treat those with a body mass index (BMI) of above 40, and in some cases where BMI is between 30 and 40, if the patient has additional health problems such as T2DM.

Epidemiology of obesity

Overweight and obesity are principal risk factors of T2DM. In the UK, the number of people classified as obese has doubled over the past 20 years and continues to rise. According to data from the 2014 Health Survey for England, 24% of adults in England are obese and a further 36% are overweight. In 2015, there were 440,288 admissions to England's hospitals for which obesity was the main reason or a secondary factor.

Data from the National Child Measurement Programme (NCMP), suggest 10% of children in the UK are obese by the time they start primary school, and 25% are so by the time they finish. 6% of people in the UK are living with diabetes of which 90% have T2DM. Over the past decade the incidence rate of T2DM has increased by 65%.

The situation is similar in the US, where 36% of adults are obese, and 6.3% have extreme obesity. Almost 74% of adults are considered either overweight or obese. Over the past 30 years, childhood obesity has more than doubled, and it has quadrupled in adolescents. The percentage of children who were obese increased from 7% in 1980 to nearly 18% in 2012. 9.3% of people in the US are living with diabetes.

The World Health Organization warns that obesity is, “one of the most serious global public health challenges of the 21st century”.

Causes of obesity

There are many complex behavioural and societal factors that combine to contribute to the causes of obesity. At its simplest, the body needs a certain amount of energy (calories) from food to keep up basic life functions. When people consume more calories than they burn, their energy balance tips toward weight gain, excess weight, and obesity. In the videos below Mohammed Hankir, Department of Medicine, University of Leipzig, Germany, describes what causes obesity, and the relationship between obesity and T2DM:

What are the causes of obesity?

What is the relationship between obesity and type-2 diabetes?

The cost of diabesity

Obesity costs the UK £47bn every year. The medical care costs alone for obesity in the US are estimated to be more than US$147bn. Diabetes treatment and indirect medical costs run to £10.3bn in the UK and US$176bn in the US, representing significant increases over the past five years. The medical costs for an individual with diabetes are typically 2.5 times higher than for someone without the disease. As prevalence of obesity increases these costs will rapidly rise.

T2DM prevention and treatment

NHS England, Public Health England and Diabetes UK’s National Diabetes Prevention Program is based upon diet and exercise-induced weight loss, which sometimes remedies insulin resistance. For obese people dietary and lifestyle therapies have limited short-term and almost non-existent long-term success records. According to Professor John Wilding, Head of the Department of Obesity and Endocrinology at the University of Liverpool, UK; the problem with low calorie diets, “is that most people will lose weight, but most people will also regain much of that weight that has been lost.” The UK’s National Institute of Health and Clinical Excellence (NICE) does not support the routine use of low calorie diets.

Once an overweight or obese person has T2DM the stakes change. With the limited success of conventional medical therapies, bariatric surgery has become an increasingly popular treatment in the war against obesity and latterly also for T2DM. The 2014 UK National Bariatric Surgery Registry reported that there is good evidence from randomised controlled studies that surgery is superior to medical therapy in improving diabetes control and metabolic syndrome. Surgery lowers the number of hypoglycaemic medications needed, including some people no longer needing insulin. It also means many people living with T2DM going into remission, and it markedly lowers the incidence of T2DM compared to matched-patients not having surgery.

NICE guidelines for bariatric surgery as a therapy for diabesity

Concerned about the rising prevalence of diabesity (obesity and diabetes) and the limited success of conventional strategies, in 2011, the International Diabetes Federation endorsed bariatric surgery as a T2DM treatment for obese people. The Federation’s endorsement is a validation of research and medical experience showing that surgery to reduce food intake can alter the biochemistry of the entire body. It also marked the beginning of a major new assault on diabetes.

In 2014, NICE introduced guidelines for bariatric surgery as a treatment option for obese adults, and suggested that it would greatly help T2DM. Current NICE guidelines state that bariatric surgery should be offered to anyone who is morbidly obese (a BMI of 40 or over), to those with a BMI over 35 if they have another condition, such as T2DM, and to those with a BMI of at least 30 with a recent diagnosis of diabetes.

In the UK only about 6,500 people each year have bariatric surgery. This is significantly lower than other European countries, which perform on average about 50,000 stomach reduction surgeries each year. Under the NICE guidelines, up to 2m people would be eligible for free bariatric surgery on the NHS, which would cost the taxpayer £12bn.

Biggest breakthrough in diabetes care since the introduction of insulin

In 2016 a review written by a group of researchers led by David Cummings, an endocrinologist at the University of Washington set out guidelines for bariatric surgery as a treatment option for diabetes. Francesco Rubino, one of the experts behind the guidelines and professor of metabolic and bariatric surgery at King's College London, said: “This is the closest that we have ever been to a cure for diabetes. It is the most powerful treatment to date.” Other doctors who drew up the guidelines said such changes could amount to the most significant breakthrough in diabetes care since the introduction of insulin in the 1920s.

The modern Roux-en-Y gastric bypass

The ‘gold standard’ bariatric surgical procedure is the Roux-en-Y Gastric Bypass, which is the most commonly performed bariatric procedure worldwide, named after a 19th century Swiss surgeon César Roux, who first performed the surgery to reroute the small intestine. The modern version of the procedure involves reducing the stomach to a little pouch, to curb eating and appetite, and then connecting that pouch to a lower section of the intestine. By using less of the intestine, fewer nutrients are absorbed, and the patient loses weight.

Until recently it has been poorly understood why, after bariatric surgery, a significant proportion of patients with T2DM leave hospital either needing no insulin, or lower doses, before ever losing any weight. Re-plumbing the GI-tract appears to reprogram the body’s hormones and resets its metabolism.

Advances in bariatric surgery

Thirty years ago there was little interest in bariatric surgery, which was risky, and not widely practiced. It involved a large, bloody incision, the prising apart of the heavy, fatty abdominal walls with metal arms, which then had to be held in place while the surgeon carried out procedures deep in the gut. Patient recovery times were long, and the risk of complications high.

By the first decade of the 21st century, when obesity became an epidemic in advanced economies the relationship between bariatric surgery and T2DM was given more attention. The medical device industry developed new surgical tools to facilitate blood free minimally invasive procedures for obese people, but researchers were still struggling to understand why bariatric surgery “cured” diabetes.

Understanding why bariatric surgery cures diabetes

One of the scientists to discover why bariatric surgery cures T2DM is Blandine Laferrère, an endocrinologist at the New York Obesity Nutrition Research Center at St. Luke’s. Our gut hormone ghrelin signals to our brain that we are hungry and to start eating. Receptors in out GI tract signal to our brain that we are full and to stop eating. In obese people such signalling malfunctions, and leaves them perpetually hungry. According to Laferrère, “It just happened that the surgeons did this type of surgery for weight loss, and that turned out to have a spectacular effect on the remission of T2DM.”

Further research was undertaken by Laferrère and influenced by Werner Creutzfeldt, a German doctor who published work on gut hormones that increased stimulation of insulin secretion, which he called an “incretin effect”. According to Laferrère, bariatric surgery, rather than actual weight loss, stimulates the incretin effect, which boosts the production of insulin while lowering the symptoms of diabetes. She concluded that the surgery itself triggered the hormone network, which diet-induced weight loss could not provide.

Takeaways

Scientists claim that bariatric surgery is the biggest step forward in diabetes treatment in 100 years, and suggest we are no longer talking about the treatment of obesity, but treatment of diabetes.